HIV CNS disease is characterized by activation of macrophages/microglia in the brain and production of proinflammatory cytokines and proapoptotic/neurotoxic mediators that leads to neuronal loss. While highly active antiretroviral therapy (HAART) has been successful in improving the quality of life for most HIV-infected individuals, there can be a surprising degree of ongoing neuroinflammation in the brains of patients on HAART. As a result, there still is a need to identify therapeutics that will control CNS inflammation. The immune status of the periphery is central to the development of HIV-associated neurological disease in the brain. Continued stimulation of the innate immune system characterized by ongoing production of IFNa and as well as IDO during HIV infection is thought to be responsible for increased activation and proliferation of T cells, loss of T cells and inhibition of T cell function, eventually leading to immune exhaustion. Minocycline is a safe and effective antibiotic that has potent anti-inflammatory and neuroprotective activities, inhibits HIV/SIV replication in macrophages and lymphocytes and ameliorates the severity of CNS inflammation and neurodegeneration in SIV-infected macaques. This occurs at least partly by reducing production of Type I IFNs and suppressing activation of lymphocytes and monocytes/macrophages, thus reducing the number of cells that traffic to the brain. Interestingly, one of the major characteristics of natural hosts for SIV infection such as sooty mangabeys and African green monkeys, which can be infected but do not get AIDS, is that they have significantly fewer activated lymphocytes in the peripheral blood. Our hypothesis is that minocycline, by suppressing chronic, unregulated innate immune responses, thus reducing the activation and proliferation of lymphocytes, acts by pharmacologically converting the non-natural host's anti-viral immune responses to those of a natural host, thus preventing immune exhaustion and maintaining systemic immune function. This reduces trafficking of T cells and macrophages to the CNS, thus reducing the severity of CNS disease. Aim 1 of this application is to determine whether administration of minocycline to SIV-infected macaques beginning immediately after acute infection suppresses the chronic unregulated activation of innate and adaptive immune responses in both the periphery and the brain, reducing expression of Type I IFNs and IDO, the number of activated lymphocytes and macrophages and virus replication in the brain. Aim 2 is to determine whether treatment of animals with minocycline prior to infection with SIV normalizes innate immune responses to the virus and reduces or abrogates virus infection of the CNS. Aim 3 is to determine the extent to which the calcium binding, antioxidant or membrane association properties of minocycline contribute to its ability to suppress lymphocyte and macrophage activation and SIV replication.